4-Alkenyl-2-aminothiazoles: Smart Dienes for Polar [4 + 2] Cycloadditions

Abstract

An exhaustive investigation on the [4+2] cycloadditions of 4-alkenyl-2-aminothiazoles with a wide range of dienophiles has been carried out. 4-Alkenyl-2-aminothiazoles act as good in-out dienes reacting with dienophiles bearing electron-withdrawing groups. The heteroannulations, typically conducted under mild conditions, are endo-selective when cyclic dienophiles are employed and regioselective when the reactions are conducted with non symmetric dienophiles. The endo-selective processes presumably take place by concerted but highly asynchronous mechanisms. By contrast, the low levels of endo selectivity and the lack of stereospecificity in the reactions with certain acyclic dienophiles point to a stepwise mechanism with a zwitterion as the most plausible intermediate. The course of the reaction changes when the highly reactive PTAD and TCNE are used as dienophiles since only addition products are obtained. Calculations of the HOMO and LUMO energy values of representative 4-alkenyl-2-aminothiazoles and the results of π-facial diastereoselective processes by using chiral substrates are also disclosed.